T cells are activated by engagement of their T cell receptor (TCR) by specific MHC-peptide complexes expressed on antigen-presenting cells, but other signals concurrently delivered decide the appropriate immune response. CD28 represents the archetype of activating costimulatory receptor (Carreno & Collins (2002) Annu. Rev. Immunol. 20:29-53; June, et al. (1987) Mol. Cell. Biol. 7:4472-4481; Thompson, et al. (1989) Proc. Natl. Acad. Sci. USA 86:1333-1337), but many other molecules contribute to support continued expansion and differentiation of T cells (Watts (2005) Annu. Rev. Immunol. 23:23-68; Markiewicz, et al. (2005) J. Immunol. 175:2825-2833; Groh, et al. (2001) Nat. Immunol. 2:255-260; Conejo-Garcia, et al. (2004) Cancer Res. 64:2175-2182; Conejo-Garcia, et al. (2003) Cancer Biol. Ther. 2:446-451; Kahn & Koretzky (2006) Nat. Immunol. 7:1286-1288). In this context, the extent of naïve T cell proliferation is critically dependent on the cytokine milieu (Swain (1995) J. Leukoc. Biol. 57:795-798; Boyman, et al. (2006) Science 311:1924-1927).
Experimental results indicate that engagement of CD161, a C-type lectin receptor associated with NK cells (Lanier, et al. (1994) J. Immunol. 153:2417-2428), enhances IFN-γ and TNF-α production in the context of a TCR signal (Takahashi, et al. (2006) J. Immunol. 176:211-216; Aldemir, et al. (2005) J. Immunol. 175:7791-7795), while inducing the production of IL-12 by dendritic cells (Poggi, et al. (1997) Eur. J. Immunol. 27:2965-2970). Unlike murine lymphocytes, the expression of CD161 in human T cells identifies mostly memory lymphocytes, but only a small proportion of invariant NK T cells (Takahashi, et al. (2006) supra). The only previously identified ligand of CD161 is CLEC2D/LLT1 (Aldemir, et al. (2005) supra; Rosen, et al. (2005) J. Immunol. 175:7796-7799), another C-type lectin molecule mapping in the vicinity of NKG2D at the NK cluster. This narrow region of human chromosome 12 spans ˜2 Mb and contains at least 18 different genes involved in immune responses that encode for leukocyte receptors exhibiting a C-type lectin-like motif in their extracellular part.